Endothelial Damage in Sepsis: The Importance of Systems Biology.

The early diagnosis and appropriate stratification of sepsis continues to be one of the most important challenges in modern medicine. Single isolated biomarkers have not been enough to improve diagnostic and prognostic strategies and to progress toward therapeutic goals. The information generated by the human genome project has allowed a more holistic approach to the problem. The integration of genomics, transcriptomics, proteomics and metabolomics in sepsis has allowed us to progress in the knowledge of new pathways which are pathophysiologically involved in this disease. Thus, we have understood the importance of and complex interaction between the inflammatory response and the endothelium. Understanding the role of important parts of the microcirculation, such as the endothelial glycocalyx and its interaction with the inflammatory response, has provided early recognition elements for clinical practice that allow the rational use of traditional medical interventions in sepsis. This comprehensive approach, which differs from the classical mechanistic approach, uses systems biology to increase the diagnostic and prognostic spectrum of endothelial damage biomarkers in sepsis, and to provide information on new pathways involved in the pathophysiology of the disease. This, in turn, provides tools for perfecting traditional medical interventions, using them at the appropriate times according to the disease's pathophysiological context, while at the same time discovering new and improved therapeutic alternatives. We have the challenge of transferring this ideal scenario to our daily clinical practice to improve our patients' care. The purpose of this article is to provide a general description of the importance of systems biology in integrating the complex interaction between the endothelium and the inflammatory response in sepsis.

Free software to analyse the clinical relevance of drug interactions with antiretroviral agents (SIMARV®) in patients with HIV/AIDS.

BACKGROUND: Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. OBJECTIVE: The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. METHODS: A comprehensive Medline/PubMed database search of drug interactions was performed. Articles that recognized any drug interactions in HIV disease were selected. The publications accessed were limited to human studies in English or Spanish, with full texts retrieved. Drug interactions were analyzed, assessed, and grouped into four levels of clinical relevance according to gravity and probability. Software to systematize the information regarding drug interactions and their clinical relevance was designed and developed. RESULTS: Overall, 952 different references were retrieved and 446 selected; in addition, 67 articles were selected from the citation lists of identified articles. A total of 2119 pairs of drug interactions were identified; of this group, 2006 (94.7%) were drug-drug interactions, 1982 (93.5%) had an identified pharmacokinetic mechanism, and 1409 (66.5%) were mediated by enzyme inhibition. In terms of clinical relevance, 1285 (60.6%) drug interactions were clinically significant in patients with HIV (levels 1 and 2). With this information, a software program that facilitates identification and assessment of the clinical relevance of antiretroviral drug interactions (SIMARV®) was developed. CONCLUSIONS: A free software package with information on 2119 pairs of antiretroviral drug interactions was designed and developed that could facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS.

[Approach to establishing and evaluating clinical relevance of drug interactions in HIV patients: 2009 update]. / Aproximación para establecer y evaluar la relevancia clínica de las interacciones medicamentosas en pacientes infectados con virus de la inmunodeficiencia humana: actualización 2009.

OBJECTIVE: To update information on drug interactions in patients with HIV/AIDS. METHOD: PubMed was used to review English and Spanish articles published between 1 July 2007 and 30 April 2009 on antiretroviral drug interactions in humans. The search included a review of interactions between commonly-used medications in patients with HIV/AIDS and references from articles considered to be relevant. RESULTS: 52 new interactions were identified having to do with CYP3A4 metabolism and competition for intestinal absorption. New pharmacokinetic interactions were identified for medications that were already on the market, and we report interactions for drugs that were recently introduced: Tipranavir, Fosamprenavir, Darunavir, Raltegravir, Maraviroc and Etravirine. CONCLUSIONS: There is evidence of 52 new interactions between medications using metabolic routes in the CYP450 enzymatic system, and an explanation is given for others in the intestinal absorption process.

Effect of zinc replacement on lipids and lipoproteins in type 2-diabetic patients.

Abnormal zinc and lipid plasma levels occur more frequently in metabolically uncontrolled diabetic patients. These lipid alterations are key factors in the emergence of microvascular complications, which lead to death in those patients. Yet, zinc sulfate supplementation may be a therapeutical resource to recover some functioning and improve life span. This article reports the assessment of lipid profile from type 2-diabetes mellitus patients treated with hypoglycemic therapy drugs, who additionally presented zinc levels lower than average in Mexican reference. The patients received a 100 mg zinc sulfate treatment in a crossover double-blind design of clinically controlled study with starch as placebo. The diabetic patients had changes in their lipid profile after a 12-week zinc treatment as compared with placebo treatment. The 100 mg zinc sulfate treatment was well tolerated, significantly reduced total cholesterol and triglyceride concentrations, and increased those corresponding to zinc as well as HDL cholesterol in the bloodstream. Thus, using this treatment the cardiovascular involvement is expected to decrease in the type 2-diabetes mellitus patients, especially those with myocardial infarction and stroke, which are the main death causes in Mexico.

Correlation between serum leptin levels and insulin sensitivity in diffuse toxic goiter.

OBJECTIVE: The aim of this survey was to assess the correlation between leptin and insulin sensitivity (IS) in cases of diffuse toxic goiter. DESIGN, PATIENTS, MEASUREMENTS: This is a descriptive study on patients with diffuse toxic goiter (DTG) assessing their body mass index (BMI), serum leptin concentrations, circulating insulin (area under the curve (AuC) of insulin), average insulin level, thyroid hormones, thyroid stimulating hormone (TSH), glycemia and IS (using a hyperinsulinemic-euglycemic clamp and the homeostasis model for assessment of insulin resistance (HOMA-IR) before and after euthyroidism induced with metimazol. RESULTS: The average patient age was 35 years old (range 31-40 years), height was 157 cm (range 151-160 cm), glycemia was 4.3 +/- 0.3 mmol/L and TSH 0.1 +/- 0.1 microU/mL. Average leptin level was 11.3 +/- 2.8 ng/dL, the average insulin level was 10.13 +/- 3.7 mIU/mL and the AuC for insulin was 50.6 +/- 18 microIU x min/mL. No correlation was found between leptin and BMI, thyroid hormones and glycemia. While controlling for the BMI effect, a correlation was found between leptin and TSH (r = -0.77, p = 0.042), as well as between leptin and insulinemia (r = 0.93, r2 = 0.86, p = 0.001) independently from the state of thyroid function. There was a tendency for a high correlation between leptin and the insulin AuC (hyperthyroidism: r = 0.89, p = 0.056; euthyroidism: r = 0.99, p = 0.056). A negative correlation was found between IS and the insulin AuC (rho = -0.58, p = 0.18). There was a high tendency for correlation between leptin and IS when the BMI effect (HOMA-IR: r = 0.70, p = 0.12; PHE: r = -0.55, p = 0.26) was taken into consideration. CONCLUSIONS: There is a high tendency for a negative correlation between leptin and IS when the BMI effect is controlled. There is a high tendency for a positive correlation between leptin and insulin and TSH.

Methylenetetrahydrofolate reductase (MTHFR) allele frequencies in Amerindians.

Neural tube defects (NTDs) have been associated with abnormalities of folate metabolism. Methylenetetrahydrofolate reductase (MTHFR) is the regulatory enzyme for the conversion of homocysteine to methionine. The C677T mutation in the MTHFR gene affects folate distribution, and homozygosity for the T allele may be associated with an increased risk of NTDs. A second mutation, an A1298C transversion in this same gene, is also associated with an increased risk for NTDs but only in conjunction with the 677T allele. A low incidence of NTDs has been observed in high-altitude populations; however, these studies did not provide information about the allele distribution of genes involved in folate metabolism. This investigation compares allele frequencies of the C677T and A1298C polymorphisms between Quechua people living at 3200-4200 m in the Peruvian Central Andes and an Aché group living at low altitude. Allele frequencies at both loci were not significantly different between the two populations. The absence of the 677T/677T genotypes and of the 677T/1298C arrangement in both groups may indicate a genetic contribution to reduced risk for NTDs; however, factors other than altitude are likely responsible for the low variant allele frequencies in these populations.

Beta-globin gene cluster haplotypes in two North American indigenous populations.

Haplotypes derived from five polymorphic restriction sites were determined in 50 Carrier-Sekani and 70 Mvskoke chromosomes, and the results were integrated with those previously obtained for 11 South American Indian populations. Eleven haplotypes were identified in the Mvskokes, while five were observed in the Carrier-Sekani. As in South American natives, haplotype 2 (+----) and 6 (-++ -+) were the most prevalent among the Mvskoke (46% and 30%, respectively). In the Carrier-Sekani, haplotype 2 was also the most common, but haplotype 5 (-+ -++) was somewhat more frequent (18%) than 6 (12%). High heterozygosities, as well as genetic differentiation, were observed among these two North American and two other South American groups (Mapuche and Xavante). They could be due to non-Indian admixture in the Mvskoke and Mapuche, but the findings in the other two populations require some other type of explanation.

Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population.

The beta2-adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2-adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na-Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old-world and new-world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over-represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been associated with body mass index; however no clearly defined metabolic phenotype has been established. In addition, we sequenced the coding region of the gene in three unrelated Quechua to determine if there were any other polymorphisms common in this population. None were detected.

Angiotensin-converting enzyme (ACE) alleles in the Quechua, a high altitude South American native population.

Recently it was reported that an allelic variant of the gene encoding angiotensin-converting enzyme (ACE) was significantly over-represented in a cohort of elite British mountaineers. It was proposed that this may be evidence for a specific genetic factor influencing the human capacity for physical performance. The implication that this allele could enhance performance at high altitude prompted us to determine its frequency in Quechua speaking natives living at altitudes greater than 3000m on the Andean Altiplano in South America. We found that the frequency of the putative performance allele in the Quechuas, although significantly higher than in Caucasians, was not different from lowland Native American populations. This observation suggests that, although the higher frequency of the 'performance allele' may have facilitated the migration of the ancestral Quechua to the highlands, the ACE insertion allele has not been subsequently selected for in this high altitude population.

Beta-fibrinogen allele frequencies in Peruvian Quechua, a high-altitude native population.

Elevated hematocrits, which are found in many high-altitude populations, increase the oxygen-carrying capacity of blood and may represent an adaptation to hypoxic environments. However, as high hematocrit increases blood viscosity, which in turn is associated with hypertension and heart disease, it may be advantageous for high-altitude populations to limit other factors that contribute to increased blood viscosity. One such factor is the plasma concentration of the coagulation protein fibrinogen. Several common polymorphisms in the beta-fibrinogen gene have been identified that affect fibrinogen concentrations. We determined the allele frequencies of three of these polymorphisms (G/A-455(HaeIII), C/T-148(HindIII), and G/A+448(MnlI)) in sample groups drawn from three populations: Quechua-speaking natives living at over 3,200 m in the Peruvian Andes, North American natives (Na-Dene) from coastal British Columbia, and Caucasian North Americans. The frequencies of the alleles previously shown to be associated with increased fibrinogen levels were so low in the Quechuas that their presence could be accounted for solely by genetic admixture with Caucasians. Frequencies in the Na-Dene, a Native American group unrelated to the Quechua, were not significantly different from those in Caucasians.

Languages, geography and HLA haplotypes in native American and Asian populations.

A number of studies based on linguistic, dental and genetic data have proposed that the colonization of the New World took place in three separate waves of migration from North-East Asia. Recently, other studies have suggested that only one major migration occurred. It is the aim of this study to assess these opposing migration hypotheses using molecular-typed HLA class II alleles to compare the relationships between linguistic and genetic data in contemporary Native American populations. Our results suggest that gene flow and genetic drift have been important factors in shaping the genetic landscape of Native American populations. We report significant correlations between genetic and geographical distances in Native American and East Asian populations. In contrast, a less clear-cut relationship seems to exist between genetic distances and linguistic affiliation. In particular, the close genetic relationship of the neighbouring Na-Dene Athabaskans and Amerindian Salishans suggests that geography is the more important factor. Overall, our results are most congruent with the single migration model.

Mitochondrial DNA polymorphisms in Carib people of Belize.

Analysis of mitochondrial DNA (mtDNA) control region polymorphisms in 28 Carib people of Belize, former British Honduras, revealed high levels of genetic admixture with West African populations. A previously characterized length mutation consisting of a deletion of nine base pairs in an intergenic mtDNA region was observed in two of the individuals. Phylogenetic analysis of mtDNA control region sequences associated with the mutation suggested that it arose independently in different geographical locations. Whereas in one individual the deletion reflects the Amerindian ancestry of the Caribs, in the second case it seems to be of African origin, as it occurred in conjunction with an mtDNA type found in sub-Saharan Africa. Our results agree with historical accounts on the origins of the Caribs of Belize.

[The School of Medicine of the Universidad de La Frontera]. / Facultad de Medicina de la Universidad de La Frontera.

The School of Medicine of Universidad de La Frontera is the result of a tight relationship between teaching and patient care. Its recent development is based on the strengthening of international bonds. Curricular innovation is an important accomplishment, mandated by the strategic setting up of its academic corps. The aim of undergraduate teaching is to train health professionals able to successfully face prevalent health problems, with health team management capabilities, that work in close relationship with the community, with continuous educational, research, communicational and learning skills and with a solid ethical and humanitarian education. Student based education using priority health problems as models, small group tutorials and community training are the bases of medical training for the next century.

Phylogenetic analysis of mtDNA lineages in South American mummies.

Some studies of mtDNA propose that contemporary Amerindians have descended from four haplotype groups, each defined by specific sets of polymorphisms. One recent study also found evidence of other potential founder haplotypes. We wanted to determine whether the four haplotypes in modern populations were also present in ancient South American aboriginals. We subjected mtDNA from Colombian mummies (470 to 1849 AD) to PCR amplification and restriction endonuclease analysis. The mtDNA D-loop region was surveyed for sequence variation by restriction analysis and a segment of this region was sequenced for each mummy to characterize the haplotypes. Our mummies exhibited three of the four major characteristic haplotypes of Amerindian populations defined by four markers. With sequence data obtained in the ancient samples and published data on contemporary Amerindians it was possible to infer the origin of these six mummies.

Leptospirosis sistémica: una etiología de falla multiorgánica en un caso / Systemic leptospirosis: an etiology of de multiple organ failure in 1 case

Leptospirosis is a world-spread zoonosis that is incidentally acquired by humans. It causes a diphasic febrile illness in which the Weil syndrome is its severest form, with renal, hepatic, clotting and central nervous system involvement. We report a 73 years old male, that was admitted to an intensive care unit with multiple organ failure due to leptospirosis. The clinical picture initially resembled a sepsis due to biliary tract obstruction and was operated, not finding a biliary tract obstruction. Considering the history of a fall to sewed waters, leptospirosis was suspected and treatment with penicillin was started, obtaining a full recovery of the patient

Validación de un instrumento de tamizaje para el estudio de la prevalencia de enfermedades cerebrovasculares en la población chilena / Assessment of a screening instrument to study the prevalence of cerebrovascular diseases in the chilean population

We assessed a screening instrument, adapted from a model suggested by WHO, aimed to perform population studies on the prevalence of cerebrovascular disease in Chile. Sixty-two subjects, 31 with cerebrovascular diseases and 31 without, were asked about symptoms and requested to do simple movements by trained interviewers. The results of the instrument were compared with a neurological examination performed by two specialists. Global sensitivity and specificity of the instrument, using WHO evaluation criteria, were 100 and 38.7 percent respectively. When three or more symptoms and one positive sign were considered as cutoff points, global specificity increased to 61 percent and sensitivity decreased to 93 percent. It is concluded that the present instrument is highly sensitive but lacks specificity

Disección de arteria vertebral: presentación de un caso y revisión de la literatura / Vertebral artery disection: 1 case report and literature review

Vertebral artery dissection seems to be a frequent cause of stroke in young adults. We report a 34 years old female that suffered a cardiac arrest while practicing aerobics, with complete recovery and four months later developed an acute Wallenberg`s syndrome. Magnetic resonance imaging showed an infarction in the right cerebellar hemisphere. Angiography revealed an occlusion of the third segment (V3) of the right vertebral artery which was hypoplastic. The patient was anticoagulated with a favorable clinical outcome. A follow up angiography, performed six months later, showed an incomplete recanalization of the vessel. Vertebral artery dissection should be suspected in every patient with ischemic symptoms or signs related to the vertebrobacilar territory, specially in young or middle aged patients with a history of trauma. magnetic resonance imaging and ultrasound-doppler examinations are the diagnostic test of choice

Evidence of mitochondrial DNA diversity in South American aboriginals.

The absence in South American aboriginals of an Asian-specific marker, a 9-bp deletion between the genes for the second subunit of cytochrome oxidase II and lysine transfer RNA in region V, has been interpreted as a bottlenecking effect at the Isthmus of Panama during the peopling of the Americas. We screened mitochondrial DNA (mtDNA) for this 9-bp tandem repeat and for polymorphisms in specific regions of the mtDNA in 2 ancient and 31 contemporary samples from South American aboriginals. We found additional (mtDNA) diversity in South American aboriginals in three ways. First, an Asian-specific marker not previously reported in South American aboriginals was identified by a sequencing analysis in both the contemporary Andean and Amazonian aboriginal peoples. Second, two new haplotypes so far unique to South American aboriginals were found. Additionally, we show that South American aboriginals fall into discrete populations. These results suggest that the prehistoric colonization of South America is the outcome of multiple migrations; the data do not support a bottlenecking effect at the Isthmus of Panama.